The Action of Thyroid Hormones on BMR

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1 The Action of Thyroid Hormones on BMR Signalling in Health and Disease Helen Christian HT 2011 The Thyroid gland Regulates metabolism in virtually all tissues Is of fundamental importance for the development of the CNS in the fetus and newborn Thyroid disorders are common affect 5% of women and 0.5% of men Developmental effects of T3 lungs: stimulates surfactant production and lung maturation ti (with glucocorticoids) id CNS: essential for postnatal growth of CNS stimulates myelin production, axonal growth; cochlear development bone: stimulates linear growth (via chondrocytes) bone: stimulates linear growth (via chondrocytes) stimulates normal development, maturation, eruption of teeth 1

2 Cretinism Poor neural development Stunted growth Can be treated by giving thyroid hormone at birth Iodide is scarce and insufficient supply is a major health problem in many parts of the world What is the Basal Metabolic Rate (BMR)? The minimum i calorific requirement needed d to sustain life in a resting individual Therefore, the amount of energy your body would burn if you slept all day (24h) A major component of total energy expenditure whether resting or working (60-75%) Thermogenesis mechanisms to keep core body temperature constant Obligatory thermogenesis the heat loss from regular metabolism Thermogenesis mechanisms to keep core body temperature constant Facultative or adaptive thermogenesis Extra adaptive heat loss to generate more heat eg in cold Mammals brown adipose tissue BAT non-shivering thermogenesis activated by sympathetic nervous sytem BMR is the closest expression of resting obligatory thermogenesis if BMR increases, heat production increases 23 C in man 2

3 How is Basal Metabolic Rate (BMR) measured? Whole animal indirect calorimetry Rarely measured directly, prediction equations used: General calculation: BMR (kcals) = Body weight (in lbs) x 10 kcal/lb O 2 consumption and CO 2 generation measured Harris-Benedict equation: calculation takes into account height and age WHO 1985 Age Height Growth Factors that affect BMR Fasting/starvation Body composition Temperature Aging lowers Tall, thin people high Children and pregnant women high lowers fat lowers, lean mass increases cold raises Cellular reactions which make up BMR obligatory thermogenesis Sustain ventilation and circulation in minimal state, maintain stable core body temperature Increase ATP usage Protein turnover Ion movement across the plasma membrane Turnover of nucleic acids and lipids Reduce efficiency i of ATP synthesis Proton leak across mitochondrial inner membrane (uncoupling) increases heat loss, which forces cells to burn more fuel to maintain ATP levels for vital functions 3

4 What is uncoupling? HEAT Effects of T3 on O 2 Consumption and Heat Production Proton gradient by respiratory chain is coupled to ATP synthesis However, not all of available energy is coupled to ATP synthesis inducible proton leak by uncoupling proteins HEAT Thyroid hormone controls both obligatory and facultative thermogenesis Thyroid hormone increases O 2 consumption and heat production in all tissues except brain, spleen and testes Clinical evidence for role of thyroid in control of BMR in humans - hyperthyroidism heat intolerance; hypothyroidism cold intolerance BMR is significantly reduced in TR α + β knockout mice Thyroxine increases Na- K-ATPase mrna alpha subunit of Na-K-ATPase Δ beta subunit of Na-K-ATPase Marrif 2005 LCT= lowest critical temperature Golozoubova et al, 2004 Major consumer of ATP Also calcium ATPase unpregulated in SR McDonough et al,

5 Thyroid receptors genomic actions Rapid non-genomic actions of thyroid hormones Integrin binds T4 with much higher affinity than T3 the opposite to nuclear receptors T3 acts on nuclear receptors (Kd M) which are permanently bound to response elements (TREs) in the promotor regions of target genes. Corepressor binding to TR blocks transcription in absence of ligand Heterodimerize with RXR retinoic acid receptors; alsotr alpha and beta subtypes Physiological effects: Induction of angiogenesis Bone resorption Brain development and neuronal migration Membrane ion pumps Davis et al 2008 Effects of T3 on lipid and carbohydrate metabolism obligatory thermogenesis carbohydrate metabolism: potentiates ti t ß glycogenolysis, gluconeogenesis increases glycogenesis, glucose usage, stimulates gut uptake of glucose lipid metabolism: stimulates cholesterol breakdown and synthesis; enhances lipolysis Increase ATP consumption in futile way to generate heat Targets in mitochondria thyroid hormones reduce efficiency of ATP synthesis Mitochondria use 90% of cell oxygen Hepatocytes from hyperthyroid rats have twice the respiration rate of controls Mitochondria from hepatocytes of hyperthyroid animals have increased proton permeability compared to controls uncoupling 5

6 Uncoupling proteins UCP1: mitochondria i in Brown Adipose Tissue (BAT) adipocytes UCP2: BAT, cardiac muscle, white adipose,kidney, lung, immune system UCP3: BAT and skeletal muscle Stimulation of uncoupling by thyroid hormones Two theories Thyroid hormones act directly at the membrane to make membranes more rigid, change in phospholipid composition now disregarded Transcriptional upregulation of uncoupling proteins? T3 stimulates UCP2 and UCP3 expression in WAT and skeletal muscle BAT BAT WAT Skeletal muscle However T3 induced thermogenesis intact in UCP3 KO mouse T3 thermogenic response intact Compensation in KO? Branco et al, 1999 Gong et al 2000, J Biol Chem 6

7 Facultative thermogenesis: T3 modulates adrenergic sensitivity of adipose tissue Tissues in hypothyroid animals have reduced responsiveness to adrenergic stimulation T3 induces β3 receptor expression Effect of TR Ablation on Adrenergic Sensitivity of Freshly Isolated Brown Fat Cells Ten fold less sensitive to noradrenaline BAT thermogenic response is initiated by Nor A but need T3 for full effect Noradrenaline induces T3 production from T4 in adipocytes via type 2 deiodinase activation Golozoubova et al, 2004 Types of deiodinase Type 1 - provides T3 to plasma Location -liver, kidney Type 2 provides intracellular T3 Location -brain, pituitary, adipose Type 3 - inactivates T3 and T4 Location -brain, placenta T4 T3 Mice show cold intolerance yet plasma T3 normal is local generation therefore very important 7

8 Bile acid signalling signal of food availability that bridges nutrition with metabolism Watanabe et al Nature Bile acids also enters circulation Bile activates deiodinase type 2 in brown fat Would you use thyroxine as a way to lower weight in obese patients? Discuss with your neighbour and decide yes or no and why Bile secreted after meal to promote fat absorption Oxygen consumption increases, effect not seen in DIO2 KO mouse To support thermogenesis need energy T3 Stimulates Food Intake via the Hypothalamic Ventromedial Nucleus about 5 10% of hyperthyroid individuals have a sufficiently increased appetite to gain weight despite the catabolic thyrotoxic process, suggesting that thyroid hormones may directly stimulate feeding Control T3 Egr immediate early gene expression Kong et al 2004 Thermogenesis depends on oxygen supply to tissues - effects of T3 on the cardiovascular system increases cardiac output, rate, force, systolic blood pressure diastolic blood pressure falls because of vasodilatation 'bounding pulse' in hyperthyroidism, weak pulse in hypothyroidism Increases transcription of β receptors, Ca 2+ ATPase Trα knockout mouse Marrif et al

9 Is there seasonal variation in BMR in humans? Tibetan Nomads, live at extremes of temperature and altitude (5000m) Marked seasonal variation in food intake Few calories and no meat in Summer Winter calorific intake increases %, lots of meat Results BMR in both seasons within normal range no evidence for lower Summer BMR to compensate for low calorie intake However, body fat accumulated during the Winter Does thyroid activity increase in response to cold in man? Military recruits acclimatized to cold over 4 weeks Joy et al 1963 Increased thermogenic responses to noradrenaline Skreslet et al 1968 Increased thermal insulation by body fat Thyroid hormones and treatment of obesity Thyroid hormones have a long history in the treatment of obesity However, no longer used due to side effects: Increased heart weight Tachycardia, atrial arrhythmias Thyroid atrophy Loss of lean body mass Bone loss Summary Thyroid hormones important for many physiological i l processes Primary regulator of basal metabolic rate but little is understood regarding exact mechanisms of control Therapeutic uses of thyroxine in obesity limited by side effects 9